Standard therapies are not capable of curing patients with malignant glioma; more than 90% of patients die within 2 years after diagnosis. Gene therapy appeared as a promising new approach for this disease. However, results of clinical trials with replication deficient viral vectors were disappointing. The main reasons being poor transduction efficiency of adenovirus towards glioma cells and limited spread and distribution of the vector in the tumour. With the increasing knowledge of viral genetics and its functions, an attractive alternative tool to kill malignant glioma cells has been developed: Replicating adenovirus as an oncolytic agent. This type of therapy, also referred to as virotherapy, has the potential to overcome some of the limitations connected with replication deficient adenoviral vectors. In this review the authors describe the latest developments in strategies that are being used to create a tumour- or glioma-selective replicating adenovirus. Special attention is given to the methods of viral delivery to an infiltrating tumour in the brain, regarding optimal dose and toxicity. Furthermore, the role of conventional antitumour treatments, such as irradiation and chemotherapy, in enhancing the effect of virotherapy is being emphasised.